Shape alterations in the striatum in chorea-acanthocytosis

Chorea-acanthocytosis (ChAc) is an uncommon autosomal recessive disorder due to mutations of the VPS13A gene, which encodes for the membrane protein chorein. ChAc presents with progressive limb and orobuccal chorea, but there is often a marked dysexecutive syndrome. ChAc may first present with neuropsychiatric disturbance such as obsessive-compulsive disorder (OCD), suggesting a particular role for disruption to striatal structures involved in non-motor frontostriatal loops, such as the head of the caudate nucleus. Two previous studies have suggested a marked reduction in volume in the caudate nucleus and putamen, but did not examine morphometric change

Whole genome sequencing for the genetic diagnosis of heterogenous dystonia phenotypes

Introduction: Dystonia is a clinically and genetically heterogeneous disorder and a genetic cause is often difficult to elucidate. This is the first study to use whole genome sequencing (WGS) to investigate dystonia in a large sample of affected individuals. Methods: WGS was performed on 111 probands with heterogenous dystonia phenotypes. We performed analysis for coding and non-coding variants, copy number variants (CNVs), and structural variants (SVs). We assessed for an association between dystonia and 10 known dystonia risk variants. Results: A genetic diagnosis was obtained for 11.7% (13/111) of individuals. We found that a genetic diagnosis was more likely in those with an earlier age at onset, younger age at testing, and a combined dystonia phenotype. We identified pathogenic/likely-pathogenic variants in ADCY5 (n = 1), ATM (n = 1), GNAL (n = 2), GLB1 (n = 1), KMT2B (n = 2), PRKN (n = 2), PRRT2 (n = 1), SGCE (n = 2), and THAP1 (n = 1). CNVs were detected in 3 individuals. We found an association between the known risk variant ARSG rs11655081 and dystonia (p = 0.003). Conclusion: A genetic diagnosis was found in 11.7% of individuals with dystonia. The diagnostic yield was higher in those with an earlier age of onset, younger age at testing, and a combined dystonia phenotype. WGS may be particularly relevant for dystonia given that it allows for the detection of CNVs, which accounted for 23% of the genetically diagnosed cases. © 2019 The Author

The structure of the tetrasialoganglioside from human brain

Autosomal dominant retinal vasculopathy with cerebral leukodystrophy is a microvascular endotheliopathy with middle- age onset. In nine families, we identified heterozygous C- terminal frameshift mutations in TREX1, which encodes a 3'-5' exonuclease. These truncated proteins retain exonuclease activity but lose normal perinuclear localization. These data have implications for the maintenance of vascular integrity in the degenerative cerebral microangiopathies leading to stroke and dementias

Measurement of bradykinesia and chorea in Huntington's Disease using ambulatory monitoring

Objectives: The feasibility of measuring bradykinesia and chorea in Huntington's Disease using a wearable sensor system (Parkinson’s Kinetigraph: PKG) developed for measuring bradykinesia and dyskinesia in Parkinson’s Disease was assessed. Methods: Unified Huntington’s Disease Rating Scales (UHDRS) and a PKG were obtained for 25 people with Huntington's Disease. Bradykinesia and Chorea Score were derived from relevant sub-scores of the UHDRS and compared with the PKG’s bradykinesia and dyskinesia scores. The PKG’s daytime sleepiness score was also used. Results: There was good correlation between Chorea Scores and the PKG’s dyskinesia score (Pearson’s ρ = 0.66). Correlation between the Bradykinesia Scores and the PKG’s bradykinesia score was also good (Pearson’s ρ = 0.51) in cases whose PKG scores were in the normal or bradykinetic range. The PKG’s bradykinesia score of 23, which is in the higher range of control subjects, separated participants into those with Independence Score ≥ 80 or < 80 and a Functional Assessment (FAS) score ≥ 18 or < 18. The PKG’s daytime sleep score was high in 44 % of participants, whose average time asleep was 21 % compared to 1.6 % in participants with a normal sleep index. Participants with high sleep scores were significantly more likely to have low Independence and TFC scores. Conclusions: Measures of bradykinesia and dyskinesia from clinical scales have acceptable correlations with those from the PKG. Continuous monitoring provides information about daytime sleep, which was associated with lower functional status. Further studies and larger sample sizes are required to confirm these findings and the utility of this measure in Huntington's Disease

A blinded, controlled trial of objective measurement in Parkinson's disease

Medical conditions with effective therapies are usually managed with objective measurement and therapeutic targets. Parkinson's disease has effective therapies, but continuous objective measurement has only recently become available. This blinded, controlled study examined whether management of Parkinson's disease was improved when clinical assessment and therapeutic decisions were aided by objective measurement. The primary endpoint was improvement in the Movement Disorder Society-United Parkinson's Disease Rating Scale's (MDS-UPDRS) Total Score. In one arm, objective measurement assisted doctors to alter therapy over successive visits until objective measurement scores were in target. Patients in the other arm were conventionally assessed and therapies were changed until judged optimal. There were 75 subjects in the objective measurement arm and 79 in the arm with conventional assessment and treatment. There were statistically significant improvements in the moderate clinically meaningful range in the MDS-UPDRS Total, III, IV scales in the arm using objective measurement, but not in the conventionally treated arm. These findings show that global motor and non-motor disability is improved when the management of Parkinson's disease is assisted by objective measurement.This information is available in spreadsheets. Funding provided by: Michael J. Fox Foundation for Parkinson's ResearchCrossref Funder Registry ID: http://dx.doi.org/10.13039/100000864Award Number: 13884Data was collected in a controlled study. Data includes a) clinical scales filled in by study particpants and by study co-ordinators; b) reports by doctors particapting in study; c) data from sensors and written interpreations of the sensor data

A Conditioned Response as a Measure of Impulsive-Compulsive Behaviours in Parkinson's Disease

<div><p>Objectives</p><p>Parkinson's Disease patients wore a device on the wrist that gave reminders to take levodopa and also measured bradykinesia and dyskinesia. Consumption of medications was acknowledged by placing the thumb on the device. Some patients performed this acknowledgement repeatedly and unconsciously. This study examines whether this behaviour reflected increased impulsivity.</p><p>Methods and Results</p><p>Twenty five participants were selected because they had i) excess acknowledgements described above or ii) Impulsive-Compulsive Behaviours or iii) neither of these. A blinded assessor applied clinical scales to measure Impulsive-Compulsive Behaviours, cognition, depression, anxiety and apathy. A Response Ratio, representing the number of acknowledgements/number of doses (expressed as a percentage) was tightly correlated with ratings of Impulsive-Compulsive Behaviours (r² = 0.79) in 19/25 subjects. Some of these patients had dyskinesia, which was higher with extraneous responses than with response indicating medication consumption. Six of the 25 subjects had high Impulsive-Compulsive Behaviour Scores, higher apathy scores, low levels of dyskinesia and normal Response Ratios. Patients without ICB (low RR) also had low dyskinesia levels regardless of the relevance of the response.</p><p>Conclusion</p><p>An elevated Response Ratio is a specific measure of a type of ICB where increased incentive salience is attributed to cues by the presence of high striatal dopamine levels, manifested by high levels of dyskinesia. This study also points to a second form of ICBs which occur in the absence of dyskinesia, has normal Response Ratios and higher apathy scores, and may represent prefrontal pathology.</p></div

Dyskinesia in the 30 minutes around each response.

<p><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0089319#pone-0089319-g002" target="_blank">Fig. 2A</a>. A segment of the daily PKG record from a person with ICB, showing expected responses (tan diamonds) and unexpected responses (red diamonds). Note that in this example, the 2 minute dyskinesia scores are mostly high. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0089319#pone-0089319-g002" target="_blank">Fig. 2B</a>. A segment of the daily PKG record from a person without ICB, showing expected responses (tan diamonds) and unexpected responses (red diamonds). Note that in this example, the 2 minute dyskinesia scores are below the median for controls. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0089319#pone-0089319-g002" target="_blank">Fig. 2C</a>. Histograms of the median dyskinesia score in the 30 minutes either side of expected (tan bars) and unexpected (red bars) response in the High RR group, the False Negative Group and in low RR Group. The histogram bars represent the median and 75^th percentile values for the subjects in each group. The median dyskinesia score in control (i.e. non PD) subjects is shown as a dotted line. Note that median dyskinesia scores of both expected and unexpected responses in the False Negative Group and the low RR subjects were below the median of controls. On the other hand, while the dyskinesia scores associated with expected responses in the correlated group were high, they were significantly higher still in the period surrounding unexpected responses. The P values associated with expected and unexpected response is shown.</p

The Response Ratio.

<p><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0089319#pone-0089319-g001" target="_blank">Fig. 1A</a>. Example of the output from one day of PKG recording from a patient who was prescribed 6 doses of levodopa/day. The green and blue dots represent the dyskinesia and bradykinesia (respectively) score, which was calculated every 2 minutes, with greater severity represented by increasing distance from the middle of the graph. The horizontal lines are the medians, 75^th percentile and 90^th percentiles of controls. The red vertical lines are when medications were prescribed and the diamonds are when the taking of medication was acknowledged. This subject provided a second acknowledgment to the 6:00 am dose shortly after the first acknowledgement (circle), thus providing 7 acknowledgments for 6 doses. The response ratio (RR) for this patient was 116% (7/6). <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0089319#pone-0089319-g001" target="_blank">Fig. 1B</a>. This subject was prescribed 7 doses/day but provided 35 acknowledgements. Note that this subject had many more dyskinesia scores at higher levels with many at the upper levels of the graph (e.g. 10:00 am to 11:00 am). The response ratio (RR) for this patient was 500% (35/7). <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0089319#pone-0089319-g001" target="_blank">Fig. 1C</a>: A plot of the QUIP score (y axis) plotted against the RR (X axis). Two groups are apparent: False Negatives (blue dots: n = 6), and a Correlated Group (Red dots: n = 19). The grey shaded area represents people whose RR was less than 137% and whose ICB score was 7.</p

Clinical Demographics and performance on Clinical Rating Scales.

<p>See text for abbreviations.</p

Latency of unexpected responses from the most recent levodopa dose.

<p>The median latency (in minutes, Y axis) of unexpected response from the most recent dose of levodopa in patients whose QUIP scores were >6 or ≤6. The median latency of unexpected responses was 75 minutes (interquartile range 59–90 minutes) in those with higher QUIP scores compared to 123 minutes (interquartile range 101–173 minutes) in those with low QUIP scores (p<0.0001: Mann-Whitney).</p